The Staphylococcus aureus superantigen SElX is a bifunctional toxin that inhibits neutrophil function

Bacterial superantigens (SAgs) induce relatively non-specific T-cell proliferation resulting in immune dysregulation associated with the pathogenesis of life-threatening infections such as toxic shock syndrome, and necrotizing pneumonia. Previously, we demonstrated that staphylococcal enterotoxin-like toxin X (SElX) from Staphylococcus aureus is a classical superantigen that exhibits T-cell activation in a Vß-specific manner, and contributes to the pathogenesis of necrotizing pneumonia. Here, we have further investigated the role of SElX in pathogenesis and found that its expression is controlled by the SaeRS two-component system known to regulate mediators of innate immune evasion. Consistent with this finding, we discovered that SElX binds to neutrophils from human and other mammalian species and disrupts IgG-mediated phagocytosis. Site-directed mutagenesis of the conserved sialic acid-binding motif of SElX abolished neutrophil binding and phagocytic killing, and revealed multiple glycosylated neutrophil receptors for SElX binding. Furthermore, the neutrophil binding-deficient mutant of SElX retained its capacity for T-cell activation demonstrating that SElX exhibits mechanistically independent activities on distinct cell populations associated with acquired and innate immunity, respectively. Finally, we demonstrated that the neutrophil-binding activity rather than superantigenicity is responsible for the SElX-dependent virulence observed in a necrotizing pneumonia model of infection. Taken together, we report the first example of a bi-functional SAg that can manipulate both the innate and adaptive arms of the human immune system during S. aureus pathogenesis.